Once at the plasma membrane, peptide-loaded MHC-II (pMHC-II) complexes are displayed for recognition by CD4 T cells. T cells are exquisitely sensitive and are capable of recognizing very small amounts of pMHC-II. We first reported that pMHC-II is constitutively associated with plasma membrane microdomains, termed lipid rafts, and that raft association increases the local density of pMHC-II to support T cell activation by small numbers of pMHC-II complexes. We have also been exploring the association of MHC-II with a family of proteins termed tetraspanins, and curiously MHC-II bound to tetraspanins also appears clustered in microdomains. We are currently using genetically-engineered mice lacking specific tetraspanin proteins to investigate the extent to which tetraspanin-binding influences MHC-II microdomain association and are examining the importance of tetraspanins in antigen presenting cell function.